SETD4 (SET domain containing 4) is a protein-lysine N-methyltransferase that catalyzes methylation of both histone and non-histone proteins to regulate diverse cellular processes 12. The enzyme primarily functions as an epigenetic regulator of cell quiescence by facilitating heterochromatin formation through H4K20me3 catalysis at gene promoter regions 1. SETD4 controls cancer stem cell (CSC) dormancy across multiple cancer types, with SETD4-defined quiescent CSCs showing resistance to chemoradiotherapy and promoting tumor relapse 1. Beyond cancer biology, SETD4 regulates antiviral interferon signaling by catalyzing TBK1 monomethylation at lysine 607, enhancing TBK1's interaction with MAVS, STING, and IRF3 to promote antiviral responses 2. In developmental contexts, SETD4-expressing cells contribute significantly to pancreatic development and regeneration following injury 3. The protein also demonstrates tumor-suppressive functions in prostate cancer by promoting H3K27me3-mediated transcriptional repression and cell cycle arrest 4. However, SETD4 expression correlates with poor prognosis in various cancers and negatively affects immune cell infiltration 5. These findings establish SETD4 as a crucial epigenetic regulator with context-dependent oncogenic or tumor-suppressive roles across different cancer types and developmental processes.